CARD15/NOD2 Is Required for Peyer's Patches Homeostasis in Mice

Abstract

BackgroundCARD15/NOD2 mutations are associated with susceptibility to Crohn's Disease (CD) and Graft Versus Host Disease (GVHD). CD and GVHD are suspected to be related with the dysfunction of Peyer's patches (PP) and isolated lymphoid follicles (LFs). Using a new mouse model invalidated for Card15/Nod2 (KO), we thus analysed the impact of the gene in these lymphoid formations together with the development of experimental colitis.Methodology/Principal FindingsAt weeks 4, 12 and 52, the numbers of PPs and LFs were higher in KO mice while no difference was observed at birth. At weeks 4 and 12, the size and cellular composition of PPs were analysed by flow cytometry and immunohistochemistry. PPs of KO mice were larger with an increased proportion of M cells and CD4+ T-cells. KO mice were also characterised by higher concentrations of TNFα, IFNγ, IL12 and IL4 measured by ELISA. In contrast, little differences were found in the PP-free ileum and the spleen of KO mice. By Ussing chamber experiments, we found that this PP phenotype is associated with an increased of both paracellular permeability and yeast/bacterial translocation. Finally, KO mice were more susceptible to the colitis induced by TNBS.Conclusions Card15/Nod2 deficiency induces an abnormal development and function of the PPs characterised by an exaggerated immune response and an increased permeability. These observations provide a comprehensive link between the molecular defect and the Human CARD15/NOD2 associated disorders: CD and GVHD.

Nucleotide-Binding Oligomerization Domain 2 Signaling Promotes Hyperresponsive Macrophages and Colitis in IL-10–Deficient Mice

“…NOD2 2/2 mice do not differ from WT mice in the development of DSS-induced colitis (4). However, NOD2 2/2 mice develop exacerbated disease in TNBS-induced colitis (69), and sensitizing mice with MDP or administration of lactobacillus peptidoglycan protects from TNBS-induced inflammation in a NOD2-dependent manner (35,70). These findings are contrary to the pathogenic role for NOD2 signaling demonstrated in this study.…”

Yersinia pseudotuberculosis induces transcytosis of nanoparticles across human intestinal villus epithelium via invasin-dependent macropinocytosis

“…16,68,69 The present study shows that inv þ Y. pseudotuberculosis can indeed induce a rapid increase in transport of nanoparticles in Caco-2 monolayers and human ileal tissues devoid of FAE. These results give further support to the notion that absorptive epithelial cells under the influence of external stimuli like enterobacteria can attain FAE-like properties, ie, start to sample antigens or exogenous, potentially proinflammatory particles from the intestinal lumen.…”

Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum

“…Unlike apparent gain-of-function NOD2 mutations associated with Blau syndrome or early onset sarcoidosis, CD-associated mutations in the NOD2 gene seem to be loss-of-function, which may likely alter host-microbe interactions through various mechanisms (13). Several studies have attempted to recapitulate CD-like intestinal inflammation using chemical inducers (such as DSS or TNBS) or adoptive transfer of hematopoietic cells in mice with Nod2 null or frame-shift mutations (14,(40)(41)(42)(43). Despite many interesting observations, these mouse models were limited due to the fact that inflammation was induced mainly in the colon, whereas in CD, NOD2 mutations are mostly associated with ileal inflammation (25).…”